Recrystallization method of etodolac

Abstract

The invention provides a recrystallization method of etodolac, and relates to the technical field of recrystallization of etodolac. The method takes methanol as a cosolvent and n-heptane as a solventing-out agent, and comprises the following specific steps: (1) under a temperature control condition, adding an etodolac raw material and methanol into a crystallization kettle while stirring; (2) adding n-heptane into the crystallization kettle at a certain dropwise adding rate, stopping dropwise adding when crystals are separated out, and stirring to grow the crystals; (3) after crystal growing is finished, adding the remaining n-heptane into the system at the same dropwise adding rate as that in the step (2), and after dropwise adding of the n-heptane is finished, continuing stirring; and (4) aging and drying to obtain the product. According to the recrystallization method provided by the invention, the recovery rate of the etodolac reaches 90% or above, and the proportion of S-(+)-etodolac in the recrystallization product of the etodolac reaches 80% or above, so that the proportion of S-(+)-etodolac in the etodolac is greatly increased, and meanwhile, the average particle size is relatively large and relatively uniform in distribution.

Description

Technical Field

[0001] The present invention belongs to the technical field of etodolac crystallization, and in particular relates to a recrystallization method of etodolac. Background Art

[0002] Etodolac belongs to the class of indoleacetic acid non-steroidal anti-inflammatory drugs, which are widely used in clinical practice for analgesia, treatment of osteoarthritis and rheumatoid arthritis, etc. Compared with other anti-inflammatory drugs, the advantage of etodolac is that it protects the gastrointestinal mucosa while exerting its efficacy, so it has been widely used in clinical practice. At present, most of the research on etodolac is focused on synthesis. For example, Chinese invention patent application CN101085778A discloses a method for preparing etodolac, which includes two steps: A. firstly hydrolyzing 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid methyl ester compound under the action of alcohol solution of water and caustic alkali, acidifying and crystallizing, and filtering to obtain crude etodolac; B. then dissolving the crude etodolac obtained by the above hydrolysis with an aqueous solution of caustic alkali, filtering, adding alcohol to the filtrate, acidifying and crystallizing, filtering, washing, and drying to obtain a refined etodolac. The advantages are: less acid and alkali usage, less three wastes, simple operation, stable process, high yield, good quality, low production cost, and suitable for industrial production. In the non-patent literature "Optimization of the Synthesis Process of Etodolac" (Zhang Naihua, Bao Guanglong, Nie Jianbing, et al. Chinese Journal of Pharmaceutical Industry, 2021, 52(04): 495-498. DOI: 10.16522 / j.cnki.cjph.2021.04.007.), o-ethyl bromobenzene (3) is used as the starting material, and o-ethyl phenylhydrazine hydrochloride (4) is obtained after hydrazine hydration and salt purification. 4 is freed under alkaline conditions and reacted with 2,3-dihydrofuran (5) catalyzed by Amberlyst 15 resin to generate 7-ethyl tryptophan (2). 2 is condensed and cyclized with 3-oxopentanoic acid methyl ester (6) without separation to obtain etodolac methyl ester (7). Finally, the target product 1 is hydrolyzed to obtain a purity of 99.91% and a total yield of 68% (based on 5). The method of preparing 2 from 3 has not been reported in the literature. The improved process is simple to operate, shortens the production cycle, has been verified by kilogram-level scale-up, and is suitable for industrial production.

[0003] However, there are few studies on the crystallization process of etodolac, and the synthesized etodolac products have problems such as small particle size and low quality. At the same time, according to the record of J.Med.Chem., 1986, 29, 871-874: the absolute configuration of the pharmacologically active racemate is S-(+)-etodolac, while R-(-)-etodolac is almost inactive, and the concentrations, apparent distribution volumes, protein binding and metabolism of the two in plasma and synovial fluid are very different. Therefore, it is urgent to provide a crystallization process of etodolac, study the crystallization process of etodolac, so as to increase the proportion of S-(+)-etodolac in the product, and at the same time make the average particle size of the recrystallized product larger than that of the raw material drug and more evenly distributed, which has practical significance. Summary of the invention

[0004] The present invention aims at the problems existing in the prior art and provides a method for recrystallizing etodolac. Methanol is used as a co-solvent and n-heptane is used as a solvent for recrystallization. The recovery rate of etodolac reaches more than 90%, and the proportion of S-(+)-etodolac in etodolac reaches more than 80%, which greatly increases the proportion of S-(+)-etodolac in etodolac. At the same time, the average particle size of the recrystallized product is larger and the distribution is more uniform.

[0005] The first aspect of the present invention is to provide a method for recrystallizing etodolac, wherein the recrystallization method uses methanol as a co-solvent and n-heptane as a solvent, and the specific steps are:

[0006] (1) under temperature control conditions, adding etodolac raw material and methanol in an amount required for the system to reach saturation at the temperature into a crystallization kettle, while stirring;

[0007] (2) adding n-heptane to the crystallization kettle at a certain dropwise rate, stopping the dropwise addition of the solvent and stirring to grow the crystals;

[0008] (3) After the crystal growth is completed, the remaining n-heptane is added to the system at the same dropwise rate as in step (2), and stirring is continued after the n-heptane is added;

[0009] (4) After aging and drying, the product is ready.

[0010] Preferably, the added volume ratio of the solvent to the co-solvent is 1.5-2.5 mL / mL.

[0011] Preferably, the temperature in step (1) is controlled by a low-temperature thermostatic bath at a temperature of 22-28°C.

[0012] Preferably, the concentration of etodolac in step (1) is 0.35-0.5 g / mL.

[0013] Preferably, the stirring rates in steps (1) to (3) are independently selected from 400-600 r / min, and the stirring time is independently selected from 5-10 min.

[0014] Preferably, the dropping rate of n-heptane in step (2) is 0.8-1.2 mL / min.

[0015] Preferably, the crystal growing time in step (2) is 1-3 hours.

[0016] Preferably, the aging time in step (4) is 1-1.5 h.

[0017] Preferably, the drying in step (4) is low-temperature and reduced-pressure drying.

[0018] Compared with the prior art, the present invention has the following beneficial effects: using methanol as a co-solvent and n-heptane as a solvent for recrystallization, the recovery rate of etodolac reaches more than 90%, and the proportion of S-(+)-etodolac in the etodolac recrystallization product reaches more than 80%, which greatly increases the proportion of S-(+)-etodolac. At the same time, the average particle size of the recrystallized product is larger and the distribution is more uniform. DETAILED DESCRIPTION

[0019] It is worth noting that the raw materials used in the present invention are all common commercially available products, and their sources are not specifically limited.

[0020] In the following embodiments:

[0021] The raw material of etodolac comes from Zhejiang Shouxin Pharmaceutical Co., Ltd., with batch number ETC-2407002 and purity of 99.9%. S-(+)-etodolac accounts for about 50%.

[0022] Determination of S-(+)-etodolac content: The S-(+)-etodolac content in the raw material or recrystallized product was determined according to the method described in the document "Caccamese, S., Direct high-performance liquid chromatography (HPLC) separation of etodolac enantiomers using chiral stationary phases. Chirality 1993, 5, 164-167."

[0023] Embodiment 1:

[0024] The recrystallization method of etodolac uses methanol as a co-solvent and n-heptane as a solvent, and the added volume ratio of the solvent to the co-solvent is 1.5 mL / mL. The specific steps are:

[0025] (1) Adding etodolac raw material and methanol into a crystallization kettle at 22°C, stirring at a stirring rate of 400 r / min and a stirring time of 5 min, the final concentration of etodolac is 0.35 g / mL;

[0026] (2) adding n-heptane to the crystallization kettle at a dropwise rate of 0.8 mL / min, stopping the dropwise addition after crystals precipitate, stirring at a rate of 400 r / min, stirring for 5 min, and growing the crystals for 1 h;

[0027] (3) After the crystal growth is completed, the remaining n-heptane is added to the system at a dropwise rate of 0.8 mL / min. After the n-heptane is added, stirring is continued for 5 min at a stirring rate of 400 r / min.

[0028] (4) Aging for 1 hour, and low-temperature vacuum drying to obtain the product.

[0029] Under these conditions, the recovery rate of etodolac was 93.7%, the proportion of S-(+)-etodolac in the etodolac obtained by recrystallization was 87.9%, the average particle size was 19.44 μm, and the coefficient of variation was 0.39.

[0030] Embodiment 2:

[0031] The recrystallization method of etodolac uses methanol as a co-solvent and n-heptane as a solvent, and the added volume ratio of the solvent to the co-solvent is 2.5 mL / mL. The specific steps are:

[0032] (1) Adding etodolac raw material and methanol into a crystallization kettle at 28°C, stirring while adding, the stirring rate is 600 r / min, the stirring time is 10 min, and the final concentration of etodolac is 0.5 g / mL;

[0033] (2) adding n-heptane to the crystallization kettle at a dropwise rate of 1.2 mL / min, stopping the dropwise addition after crystals precipitate, stirring at a rate of 600 r / min, stirring for 10 min, and growing the crystals for 3 h;

[0034] (3) After the crystal growth is completed, the remaining n-heptane is added to the system at a dropwise rate of 1.2 mL / min. After the n-heptane is added, stirring is continued for 10 min at a stirring rate of 600 r / min.

[0035] (4) Aging for 1.5 h, and low-temperature vacuum drying to obtain the product.

[0036] Under these conditions, the recovery rate of etodolac was 96.9%, the proportion of S-(+)-etodolac in the etodolac obtained by recrystallization was 88.4%, the average particle size was 17.23 μm, and the coefficient of variation was 0.41.

[0037] Embodiment 3:

[0038] The recrystallization method of etodolac uses methanol as a co-solvent and n-heptane as a solvent, and the added volume ratio of the solvent to the co-solvent is 2 mL / mL. The specific steps are:

[0039] (1) Adding etodolac raw material and methanol into a crystallization kettle at 25°C, stirring at a stirring rate of 500 r / min and a stirring time of 7 min, the final concentration of etodolac is 0.4 g / mL;

[0040] (2) adding n-heptane to the crystallization kettle at a dropwise rate of 1 mL / min, stopping the dropwise addition after crystals precipitate, stirring at a rate of 500 r / min, stirring for 6 min, and growing the crystals for 2 h;

[0041] (3) After the crystal growth is completed, the remaining n-heptane is added to the system at a drop rate of 1 mL / min. After the n-heptane is added, stirring is continued for 8 min at a stirring rate of 500 r / min;

[0042] (4) Aging for 1.2 h, and low-temperature vacuum drying to obtain the product.

[0043] Under these conditions, the recovery rate of etodolac was 97.1%, the proportion of S-(+)-etodolac in the etodolac obtained by recrystallization was 85.9%, the average particle size was 17.88 μm, and the coefficient of variation was 0.35.

[0044] Comparative Example 1:

[0045] The recrystallization method of etodolac uses methyl acetate as a co-solvent and n-heptane as a solvent, and the added volume ratio of the solvent to the co-solvent is 2 mL / mL. The specific steps are:

[0046] (1) Adding etodolac raw material and methyl acetate into a crystallization kettle at 25°C, stirring at a stirring rate of 500 r / min and a stirring time of 7 min, the final concentration of etodolac is 0.4 g / mL;

[0047] (2) adding n-heptane to the crystallization kettle at a dropwise rate of 1 mL / min, stopping the dropwise addition after crystals precipitate, stirring at a rate of 500 r / min, stirring for 6 min, and growing the crystals for 2 h;

[0048] (3) After the crystal growth is completed, the remaining n-heptane is added to the system at a drop rate of 1 mL / min. After the n-heptane is added, stirring is continued for 8 min at a stirring rate of 500 r / min;

[0049] (4) Aging for 1.2 h, and low-temperature vacuum drying to obtain the product.

[0050] Under these conditions, the recovery rate of etodolac was 82.1%, the proportion of S-(+)-etodolac in the etodolac obtained by recrystallization was 73.9%, the average particle size was 18.42 μm, and the coefficient of variation was 0.67.

[0051] Comparative Example 2:

[0052] The recrystallization method of etodolac uses methanol as a co-solvent and n-heptane as a solvent, and the added volume ratio of the solvent to the co-solvent is 2 mL / mL. The specific steps are:

[0053] (1) Adding etodolac raw material and methanol into a crystallization kettle at 25°C, stirring at a stirring rate of 300 r / min and a stirring time of 7 min, the final concentration of etodolac is 0.4 g / mL;

[0054] (2) adding n-heptane to the crystallization kettle at a dropwise rate of 1 mL / min, stopping the dropwise addition after crystals precipitate, stirring at a rate of 300 r / min, for 6 min, and growing the crystals for 2 h;

[0055] (3) After the crystal growth is completed, the remaining n-heptane is added to the system at a drop rate of 1 mL / min. After the n-heptane is added, stirring is continued for 8 min at a stirring rate of 300 r / min;

[0056] (4) Aging for 1.2 h, and low-temperature vacuum drying to obtain the product.

[0057] Under these conditions, the recovery rate of etodolac was 96.8%, the proportion of S-(+)-etodolac in the etodolac obtained by recrystallization was 83.4%, the average particle size was 17.39 μm, and the coefficient of variation was 0.75.

[0058] Comparative Example 3:

[0059] The recrystallization method of etodolac uses methanol as a co-solvent and n-heptane as a solvent, and the added volume ratio of the solvent to the co-solvent is 2 mL / mL. The specific steps are:

[0060] (1) Adding etodolac raw material and methanol into a crystallization kettle at 25°C, stirring at a stirring rate of 500 r / min and a stirring time of 7 min, the final concentration of etodolac is 0.4 g / mL;

[0061] (2) adding n-heptane to the crystallization kettle at a dropwise rate of 1 mL / min, stopping the dropwise addition after crystals precipitate, stirring at a rate of 500 r / min, stirring for 6 min, and growing the crystals for 2 h;

[0062] (3) After the crystal growth is completed, the remaining n-heptane is added to the system at a drop rate of 1 mL / min. After the n-heptane is added, stirring is continued for 8 min at a stirring rate of 500 r / min;

[0063] (4) Aging for 1.2 h, and low-temperature vacuum drying to obtain the product.

[0064] Under these conditions, the recovery rate of etodolac was 82.9%, the proportion of S-(+)-etodolac in the etodolac obtained by recrystallization was 67.9%, the average particle size was 24.88 μm, and the coefficient of variation was 0.87.

[0065] According to the results of the above embodiments and comparative examples, the type of cosolvent, the dripping rate of the solvent and the stirring speed during the experiment will affect the recovery rate of etodolac, the proportion of S-(+)-etodolac in the recrystallized product, the crystal particle size and the coefficient of variation of the recrystallized product. In Examples 1-3 of the present application, the recovery rate of etodolac reached more than 90%, and the proportion of S-(+)-etodolac in the recrystallized product of etodolac reached more than 80%, which greatly increased the proportion of S-(+)-etodolac. At the same time, the average particle size of the recrystallized product was larger and more evenly distributed. The comprehensive effect is better than that of Comparative Examples 1-3.

[0066] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for recrystallizing etodolac, characterized in that: The recrystallization method uses methanol as a co-solvent and n-heptane as a solvent, and the specific steps are: (1) under temperature control conditions, adding etodolac raw material and methanol in an amount required for the system to reach saturation at the temperature into a crystallization kettle, while stirring; (2) adding n-heptane to the crystallization kettle at a certain dropwise rate, stopping the dropwise addition of the solvent and stirring to grow the crystals; (3) After the crystal growth is completed, the remaining n-heptane is added to the system at the same dropwise rate as in step (2), and stirring is continued after the n-heptane is added; (4) After aging and drying, the product is ready.

2. The recrystallization method according to claim 1, characterized in that The added volume ratio of the solvent to the co-solvent is 1.5-2.5 mL / mL.

3. The recrystallization method according to claim 1, characterized in that The temperature in step (1) is controlled by a low temperature thermostatic bath at a temperature of 22-28°C.

4. The recrystallization method according to claim 1, characterized in that The concentration of etodolac in step (1) is 0.35-0.5 g / mL.

5. The recrystallization method according to claim 1, characterized in that The stirring rates in the steps (1) to (3) are independently selected from 400-600 r / min, and the stirring time is independently selected from 5-10 min.

6. The recrystallization method according to claim 1, characterized in that The dropping rate of n-heptane in step (2) is 0.8-1.2 mL / min.

7. The recrystallization method according to claim 1, characterized in that The crystal growing time in step (2) is 1-3 hours.

8. The recrystallization method according to claim 1, characterized in that The aging time in step (4) is 1-1.5h.

9. The recrystallization method according to claim 1, characterized in that The drying in step (4) is low-temperature and reduced-pressure drying.